PROJECT SUMMARY The overarching goal of this proposal is to develop a practical, externally controlled strategy to enhance the performance of injectable drug delivery systems for the local treatment of inoperable solid tumors. This noninvasive approach addresses the critical unmet need in local drug delivery for cancer treatment ? insufficient penetration of the drug into the tumors. Building upon a large body of work already applying ultrasound to enhance tumor drug delivery from nanoparticles, we will now explore a novel ultrasound application in enhancing delivery from intratumoral drug-eluting implants. We will test the platform approach in primary liver tumors (hepatocellular carcinoma or HCC), which continue to be difficult to treat systemically with chemotherapy and mostly cannot be resected surgically (in 80% of cases). Developing effective alternative treatments for liver cancer specifically, and for unresectable tumors in general, has the potential to have a high clinical impact, as few successful approaches are currently available. This MPI proposal combines drug delivery and acoustic physics and instrumentation expertise of two senior investigators. We also engage an interventional radiologist who treats liver tumors daily using image-guided techniques, and an expert in molecular imaging and the woodchuck model of spontaneous viral hepatitis infection-induced HCC to test the optimized treatment in the most clinically relevant animal model available. The research will be carried out in three specific aims. In Aim 1, we will develop the injectable, in situ forming implant formulations and will test a series of parameters to determine the most effective ones for acoustic enhancement of the drug distribution in acrylamide phantoms. In Aim 2, the optimized formulation and ultrasound parameters will be tested in a liver tumor model in rats to determine the extent of increase in distribution in vivo. Finally, in Aim 3, once the strategy has been thoroughly evaluated in the rat model, we will utilize ultrasound-enhanced local drug delivery to treat naturally-occurring HCC in a woodchuck model. This will serve as the ultimate demonstration of clinical relevance. At the completion of this project, we will have developed a new strategy for local treatment of inoperable solid tumors. With ultrasound enhancement, the drug delivery system which will be able to generate greater treatment volumes than previous approaches, and will thus be more effective at treating unresectable liver cancer than currently available options.